Diabetes mellitus and aging are commonly associated with increased incidence and severity of cardiovascular diseases. However, our understanding of the neural mechanisms underlying these dysfunctions is impeded by a lack of structural information on autonomic nerve terminals and the circuitry within the cardiac tissues (brain-heart connections). Vagal projections to the heart originate from a sensory ganglion, i.e., the nodose ganglion, and the two motor nuclei, i.e., the nucleus ambiguus (NA) and the dorsal motor nucleus of the vagus (DmnX). The overall goal of the present application is to determine the functional deficits of the vagal control of the heart induced by diabetes, aging or both, and to identify the damage to the cardiac neural circuitry, specifically to the vagal axonal projections to the heart. Vagal control of particular cardiac functions will be measured in two murine models of type 1 diabetes (strepozotocin-treated and transgenic OVE 26 mice). The vagal cardiac axons and terminals, glutamatergic transmission, and oxygen reactive species (ROS) within the parasympathetic system will be examined qualitatively and quantitatively using a battery of techniques that will include anterograde neural tracing, stereological counting, confocal microscopy, Neurolucida digitization, multichannel injections, dual immunohistochemistry, and intercellular measurement of ROS. These anatomical findings will be assessed in conjunction with physiological responses to enhance our understanding of structure-function relationships. Aim 1 will assess diabetes-associated attenuation of baroreflex and vagal control of the heart, and the associated structural changes of vagal projections to the heart and aortic arch, and examine whether diabetes and aging interact to induce more severe functional and anatomical damage to the vagal cardiac axons. Aim 2 will study diabetes and aging-associated changes in glutamatergic transmission within the brainstem. Aim 3 will determine ROS productions in parasympathetic neurons in diabetic and aging mice, and study whether chronic antioxidant treatment may reduce/prevent cardiovascular dysfunctions and structural damages, Collectively, the proposed experiments will provide unique insights into the remodeling of vagal outflow to cardiac tissues following long-term diabetes.